Influenza is an acute, contagious respiratory disease caused by influenza viruses that are spread through respiratory droplet transmission. Uncomplicated influenza is characterized by the abrupt onset of constitutional and respiratory symptoms that usually resolve within a week. In certain persons, influenza can aggravate existing medical conditions and lead to life-threatening complications. Influenza viruses are one of the most ubiquitous viruses in the world, affecting humans, canines, birds, bats and livestock. Influenza also has a significant impact on the elderly and on the very young. Influenza results in an economic burden, morbidity and even mortality, which are significant.
Influenza viruses are enveloped, negative-sense, RNA viruses with a segmented genome belonging to the Orthomyxoviridae family. They are classified on the basis of their core proteins into three distinct types: A, B, and C (Cox, N. J. and Fukuda K., Influenza. Infect. Dis. Clin. North Am. 12:27-38, 1998, which is hereby incorporated by reference in its entirety). Influenza A viruses can infect a range of mammalian and avian species, whereas types B (host range humans and seals) and C are essentially restricted to human beings. Influenza A and B viruses are mainly responsible for human disease with type A being the most pathogenic. The main antigenic determinants of influenza A and B viruses are two surface glycoproteins: neuraminidase (NA) and hemagglutinin (HA), both capable of eliciting immune response in human beings. HA is involved in receptor binding and membrane fusion. NA facilitates cleavage of virus progeny from infected cells, prevents viral aggregation, and aids movement through the mucosal respiratory-tract epithelium.
Three types of flu virus (A, B and C) are currently known, the type A viruses being responsible for animal and human conditions while the type B and type C viruses are especially pathogenic for humans. The type A viruses are subdivided into subtypes according to the antigenic structure of hemagglutinin (HA) and of neuraminidase (NA), which are the principal glycoproteins of the viral envelope. Eighteen subtypes of HA (H1 to H18) and 9 subtypes of NA (N1 to N11) stand out. The subtype of a type A virus is therefore defined by the HA subtype and the NA subtype which are present in the viral envelope. Wild birds and bats constitute the reservoir of all influenza A subtypes. Certain subtypes of influenza virus type A endemically or epidemically (annual epidemics) infect domestic birds (various subtypes including H5N1 and H9N2), horses (principally H3N8), pigs (principally H1N1, H3N2 and H1N2) and also humans (principally H1N1 and H3N2). Dogs, cats and other wild species can also occasionally be infected with certain subtypes (H3N8 and H5N1 in dogs; H5N1 in cats).
Interpandemic influenza vaccines are prepared from virus that is grown in fertile hens' eggs and are either inactivated or live attenuated influenza vaccines. Inactivated flu vaccines are composed of three possible forms of antigen preparation: inactivated whole virus, sub-virions where purified virus particles are disrupted with detergents or other reagents to solubilize the lipid envelope (so-called “split” vaccine) or purified HA and NA (subunit vaccine). These inactivated vaccines are currently given intramuscularly (i.m.), subcutaneously (s.c), or intranasally (i.n.). In accordance with World Health Organization (WHO) recommendations, seasonal influenza vaccines usually contain 45 μg of HA antigen from three co-circulating human strains (as measured by single radial immunodiffusion (SRD) (Wood, J. M. et al., “An improved single radial immunodiffusion technique for the assay of influenza hemagglutinin antigen: adaptation for potency determination of inactivated whole virus and subunit vaccines,” J. Biol. Stand. 5:237-247, 1977; Wood, J. M. et al., “International collaborative study of single radial diffusion and immunoelectrophoresis techniques for the assay of hemagglutinin antigen of influenza virus,” J. Biol. Stand. 9:317-330, 1981; both publications incorporated herein by reference in their entirety). They generally contain antigens derived from two influenza A virus strains and one influenza B strain (e.g., H1N1, H3N2 and B). A standard 0.5 ml injectable dose in most cases contains (at least) 15 μg of hemagglutinin antigen component from each strain. Vaccination plays a critical role in controlling annual influenza epidemics. Furthermore, during a pandemic, antiviral drugs may not be sufficient or effective to cover needs and the number of individuals at risk of influenza will be greater than in interpandemic periods. The development of a long lasting, broadly protective vaccine with the potential to be produced in large amounts and with efficient distribution and administration potential is an object of the invention.
Influenza virus infects millions each year, leading to over 200,000 hospitalizations and 20,000 deaths in the US. In addition, lethal strains of influenza arise on occasion (e.g., Spanish flu of 1918), with few effective means of treatment. Seasonal influenza vaccines afford some protection, provided that causative strains have not changed from the time of the vaccine formulation. High variability in the surface-expressed viral proteins of hemagglutinin and neuraminidase mandates yearly reformulation. The population should be re-immunized every year for effective protection. This necessity means that the cost of production is high and availability depends on the titer for each viral component of the vaccine (up to 4 different viruses comprise the current vaccine).
Recombinant cell culture methods of antigen production rather than chicken eggs have now been employed and two vaccine products have recently been FDA approved. Flucelvax is a recombinant virus preparation (3 inactivated viruses) made by mammalian cell culture. Flubloc® is a recombinant HA vaccine (3 different HA proteins) made by insect cell culture. These products seek to solve problems of vaccine supply but do not address the issues of antigenic drift that is associated with HA based vaccines.
It is an object of this invention to overcome the need and cost for yearly influenza vaccine development by providing a new influenza vaccine that will maintain potency from year to year. It is also an object of the invention to provide an influenza vaccine that will provide protection against new influenza strains. It is a further object of the invention to provide an influenza therapy for treating individuals already infected with influenza, or for prophylactic treatment of individuals.
It is also an object of the invention to reduce the severity of an influenza infection in an infected patient, and/or reduce the duration of flu symptoms in a patient infected with influenza using a composition comprising an antibody or antibody fragment that binds to an M1 polypeptide.